Inverted binding of cytosine in the active site pocket of DNMT3A

New publication in "J. Mol. Biol."

June 25, 2019 /

Mechanism of cytosine-N3 methylation catalyzed by DNMT3A

New publication in "J. Mol. Biol."

Recently, we have discovered that different DNA-(cytosine C5)-methyltransferases including DNMT3A generate low levels of cytosine methylated at the N3 position which is mutagenic (Rosic et al., Nat. Genet. 2018, 50, 452-459). This reaction resulted in the co-evolution of DNMTs and ALKB2 DNA repair enzymes, which repair N3-methylcytosine in DNA. The mechanism of the N3-methylation reaction remained elusive and it has been studied in this publication. Our data indicate that the methylation of N3 instead of C5 is caused by an inverted binding of the flipped cytosine target base into the active site pocket of the DNA methyltransferase. Given that all DNA-(cytosine C5)-methyltransferases have a common catalytic mechanism it is likely that other enzymes of this class generate 3mC following the same mechanism.



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